2-hydroxy-2-phenyl alkyl carbamates



United States Patent 3,248,4 8 Z-HYDROXY-Z-PHENYL ALKYL CARBAMATESCharles ll). Bossinger, Royal Oaks, RR. 1, Kankakee, Ill., and Kelley G.Taylor, 1312 Gayman Drive, Decatur, Ill. No Drawing. Filed June 26,1962, Ser. No. 205,198 4 Claims. (Cl. 260482) This application is acontinuation-in-part of copending application Serial No. 729,554, filedApril 21, 1958 and of Serial No. 38,763, filed June 27, 1960, nowabandoned. Application Serial No. 38,763 was a continuation-.in-part ofapplication Serial No. 729,553, filed April 21, 1958, now abandoned, andapplications Serial N-os. 729,553 and 729,554 were continuations-in-partof parent application Serial No. 554,132, filed December 20, 1955, nowabandoned.

This invention relates to certain carbamate compounds and to a method oftreating the central nervous system by administering these compounds.The novel compounds of this invention can be classified generally ashydroxy phenyl alkyl carbamate compounds, and more particularly as theclass of such compounds containing tertiary alcohol groups.

It is an object of this invention to provide carbamate compounds for usein treating the central nervous system which achieve tranquilization.with a minimum of muscle relaxation. Another related object is toprovide carbamate compounds which can be used in treating anxietystates. Still another object is to provide carbamate compounds whichcombine the effects of tranquilization and mild sedation withoutcortical depressing effects. Further objects and advantages will beindicated in the following detailed specification.

The hydroxy phenyl alkyl carbamate compounds which are useful in thetreatment of the central nervous system in accordance with the presentinvention all contain a tertiary alcohol group and are characterized bythe following structural formula:

In the foregoing formula, R is an alkyl group containing from 1 to 3carbon atoms, and R is either hydrogen or an alkyl group containing from1 to 3 carbon atoms. In one preferred sub-class of compounds R is ethyland R is hydrogen, or an alkyl group containing from 1 to 3 carbonatoms. Examples of such preferred compounds are Z-hydroxy-Z-phenyl butylcarbamate, 3-hydroxy-3- phenyl pentyl-2-carbamate, and4-hydroxy-4-phenyl hexyl- 3-carbamate. Other compounds coming within thescope of the present invention are 2-hydroxy-2-phenyl propyl carbamate,and 2-hydroxy-2-phenyl pentyl carbamate.

The foregoing compounds can be prepared by the process described incopending application Serial No. 161,739, filed December 22, 1961, nowabandoned. In that process the first step is the preparation of anorganic cyclic carbonate from which the desired carbamate compound can Ibe obtained. The cyclic carbonate can be made by dissolving a phenylethane diol in a dialkyl carbonate and heating this reaction mixture toevaporate the hydroxy alkyl reaction by-product. This leaves the organiccyclic carbonate reaction product as the residue. If desired, an alkalicatalyst may be used. The cyclic intermediate is a 4-phenyl ethylenecarbonate, which is preferably reacted with ammonia to split thecarbonate ring and form the desired carbamate. This procedure isdescribed in greater detail in the cited application Serial No. 161,739.

Other processes can be used to prepare the carbamates. In one suchprocedure, a 1,2-glycol is converted to the corresponding carbonate, andthe carbonate is subjected to an ammonolysis to obtain the desiredcarbamate. This 3,248,418 Patented Apr. 26, 1966 process was describedin prior application Serial No. 816,- 700, filed May 29, 1959, now US.Patent S.N. 3,066,164. Preferably, a 1,2-glycol is condensed with ahalo-formic ester to obtain an acyclic carbonate which is then subjectedto ammonolysis to obtain the monocarbamate. Since the particular processfor preparing the carbamate compounds. does not form a part of thepresent invention it is not believed it will be necessary to furtherdescribe such processes herein, except that the preparation of specificcarbamate compounds will be subsequently illustrated.

In utilizing the compounds of this invention for central nervous systemtreatment it is preferred to administer the compounds orally. Since thecompounds are wella'bsorbed orally, it will usually not be necessary toresort to parenteral administration. For oral administration, it ispreferred to combine the carbamate compound with a pharmaceuticalcarrier. The proportions of the carrier and carbamate compound are notcritical, and they vary considerably depending whether the compositionis to be filled into capsules or formed into tablets. In tableting, itwill usually be desirable to employ at least as much of thepharmaceutical carrier as the carbamate compound. Various ediblepharmaceutical carriers, or mixtures thereof can be used. For example, amixture of lactose, dibasic calcium phosphate, and cornstarch issuitable. Additional ingredients can be incluuded, such as lubricantslike magnesium stearate.

When administering the compounds of this invention orally for centralnervous system treatment, the total daily dose will usually fall withinthe range from 400 to 1600 miligrams of the carbamate compound per 24hour period. Typically, the daily dose will range from 600 to 800milligrams. In rare cases, it may sometimes be desirable to administeras much as 2,400 milligrams per day. In practicing the method of thisinvention, it will therefore be convenient to have the carbamatecompound combined with a pharmaceutical carrier and prepared in tabletsor other dosage unit form. Each tablet or dosage unit can contain from50 to 600 milligrams of the carbamate compound. For example, tabletscontaining 200 milligrams of the carbamate compound can be administeredeither 1 tablet three times a day to achieve a daily dose of 600milligrams or up to 2 tablets four times a day to achieve a daily doseof 1,600 milligrams.

The present invention is further illustrated by the following specificexamples.

Example 1 The following method was used in preparing 2-hydroxy-2-phenylbutyl carbamate:

2-phenyl 1, 2 butane diol in the amount of 16.6 gms. (0.1 mole) wasmixed with 11.8 gm. (0.1 mole) of diethyl carbonate and 0.1 gms. of KOHin a round bottom flask equipped with a column for distillation. Thereaction mixture was heated to 125 C. to allow take off of the resultingethanol as formed. This continued for approximately 4 hours or untilethanol removal ceased. Any excess ethyl carbonate was then removedunder vacuum.

The residue Z-phenyl butylene carbonate was then treated with ml. ofconcentrate NH OH for 4 hours at' room temperature. The amomnia is thenremoved at 40 C. under vacuum. The carbamate settled to the bottom andwas drawn off as an oil. The aqueous layer was extracted withtrichloroethylene and the oily carbonate added to this material. Afterdrying these combined materials with sodium sulfate and azeotropicdistillation to further dry the solvent, it was chilled to 0 to 5 C. Thesolid formed was collected on a Buchner and washed with coldtrichloroethylene. There was obtained 16.3 gms. of 2-hydroxy-2-phneylbutyl carbamate. (78% over all yield).

Example 2 2.16 kg. (12M) 3-pheny'l 2,3 pentanediol 1.70 k. (144) diethylcarbonate 21 gms. potasium hydroxide Using these materials the reactionwas carried out in a manner similar t Example 1 to obtain the crudecyclic carbonate and this was in turn treated with 43 pounds of 28%aqueous amonia to obtain 1.51 kg. (56%) of 3-hydroxy-3-phenyl-2-pentylcarbamate M.P. 124.5125.5 C.

Example 3 2-phenyl-1,2-propanediol, in the amount of 56 gms., was mixedwith 150 mgs. of propylene carbonate in a round bottom flask equipedwith a 25 mm. jacketed column. The resulting mixture was heated for aperiod of 14 hours at a bath temperature of 160170 C. and a pressure of35 mm. In this operation a distillate was obtained at a temperature of90-134 C. Further distill-ation at a pressure of 35 mm. yielded 160 mgs.of reaction product. This reaction product was fractionated to yield51.0 gms. of material having a boiling point of 126-128 C. at a pressureof 1.2 mm. The analysis of this reaction product was C67.39 and H-5.66.

Z-phenylpropylene carbonate, in the amount of 10.0 gms. was mixed with200 ml. of a concentrated aqueous ammonium hydroxide solution. Theresulting mixture was heated for a period of 1 hour on a steam bath. Theexcess ammonium and water were separated from the reaction product underreduced pressure. The separated reaction product, which was of theconsistency of an oil, was fractionized by distillation. The resultingproduct, 2-hydroxy-2-phenyl propyl carbonate, which was obtained in ayield of 5.15 gms., had a boiling point of 160-167 C.

Example 4 2-phenyl-1,2-pentadiol, in the amount of 40.5 gms., was mixedwith 125 ml. of propylene carbonate. The resulting mixture was incubatedin an oil bath at a temperature of 165 C. and a pressure of 33-35 mm. ofmercury for a period of 11 hours under total reflex.

The propylene glycol was then separated from the reaction mixture usinga heated fractionating column equipped with a Todd take-01f head. After7 hours the propylene glycol ceased to be distilled, and then the excesspropylene carbonate was removed from the reaction mixture. Thereafter,the pressure in the system was reduced to 0.65 mm. of mercury, and theresidual mixture fractionated to yield a reaction product having aboiling point of 128-129" C. at a pressure of 0.65 mm. of mercury. Theproduct was 2-phenyl-1,2-pentylene carbonate. 7.7 gms. (0.37 mole) ofthis product was mixed with 100 ml. of methyl alcohol. The mixture wassaturated with ammonia and heated as previously described to yield 6.0gms. (73%) of 2-hydroxy-2-phenylpentyl carbamate.

Example 3-phenyl-3,4-hexane diol 2900 g. and diethyl cadbonate 2600 gm.were placed in a 12 liter flask. The reaction mixture was stirred andmelted at 80 C. 50 gm. of powdered KOH 'was added. The temperature inthe flask Was raised to 126 C. After one to one and onehalf hours at 126C., the deaction started and a mixture of ethanol and diethyl carbonatewas distilled rapidly at up to 94 C.

After the distillation was continued for four hours,

all the volatile material was stripped off. The crude cyclic carbonate,3100 gm, was mixed with four pounds 4 of ammonia in thirteen liters ofmethanol at ice-bath temperature with stirring. The reaction mixture wasthen left standing at room temperature for 166 hours.

After all the volatile components were removed, the residual paste wasdissolved in benzene at the ratio of 1 gm. per 6 ml. The mixture wasfiltered and the filtrate was permitted to crystallize at roomtemperature. The crystalline product, being 4-hydroxy-4-phenyl-3-hexylcarbamate, was collected and dried at 60 C. in a vacuum oven for 20hours. The dried product weighed 2288 gm., a 70.5% yield, M.P. l1,6.5 C.

Example 6 Tablets for oral administration were prepared from2-hydroxy-2-phenyl carbamates. This compound was combined with a mixedpharmaceutical carrier in the ratio of 2 parts by weight of thecarbamate compound per 3 parts of the pharmaceutical carrier. The mixedcarrier contained dibasic calcium phosphate as the principal ingredienttogether with smaller amounts of lactose and 1 part of cornstarch. Asmall amount of magnesium stearate was also included.

The carbamate compound, the calcium phosphate, the lactose, and part ofthe magnesium stearate were blended and dry mixed until a uniformcomposition was obtained. This was formed into firm slugs no greaterthan A inch thick. The slugs were then put through an oscillatinggranulator equipped with a 10 mesh screen. The cornstarch and a littlemore magnesium stearate was added at intervals while the slugs werebeing sized. The granulation was blended in a drum tumbler for 30minutes. Following this, the granulation was compressed into tablets of500 mg. per tablet containing 200 milligrams of the carbamate compound.

While in the foregoing specification, this invention has been describedin relation to certain preferred embodiments, and many details have beenset forth for purpose of illustration, it will be apparent to thoseskilled in the art that the invention is susceptible to additionalembodiments, and that certain of the details set forth herein can bevaried considerably without departing from the basic principles of theinvention.

We claim:

1. Hydroxy phenyl alkyl carbamate compounds useful in the treatment ofthe central nervous system, said compounds containing a tertiary alcoholgroup and being characterized by the structural formula t Q-C-(fH-O-O-NH:

wherein R is an alkyl group containing from 1 to 3 carbon atoms and R ishydrogen.

2. The compound 2-hydroxy-2-phen7l butyl carbamate.

3. 2-hydroxy-2-phenyl propyl carbamate. 4. 2-hydroXy-2-phenyl pentylcarbamate.

References Cited by the Examiner UNITED STATES PATENTS 2,627,524 2/ 1953Malkemus 260-482 2,649,473 8/ 1953 Chenicek 260-482 2,656,378 10/1953Berger 260-482 2,890,984 6/ 1959 Sahyun 167-65 2,967,880 1/1961 Finke260482 3,036,954 5/1962 Robbins 167-65 3,066,164 11/1962 Siiferd et al260-482 LORRAINE A. WEINBERGER, Primary Examiner.

MORRIS O. WOLK, LEON ZITVER, Examiners,

1. HYDROXY PHENYL ALKYL CARBAMATE COMPOUNDS USEFUL IN THE TREATMENT OFTHE CENTRAL NERVOUS SYSTEM, SAID COMPOUNDS CONTAINING A TERTIARY ALCOHOLGROUP AND BEING CHARACTERIZED BY THE STANDARD FORMULA